PGE oximes

ABSTRACT

This invention is a class of new organic compounds having the formula   WHEREIN R1 is hydrogen or alkyl of 1 to 8 carbon atoms, inclusive, wherein Q is -OH, -OR2 wherein R2 is alkyl of 1 to 4 carbon atoms, inclusive, or -NHCONH2, wherein X is -CH2CH2- or trans-CH CH- and both Y and Z are -CH2CH2-, or wherein X is trans-CH CH-, Y is cis-CH CH-, and Z is -CH2CH2- or cis-CH CH-, wherein m is 0, 1, or 2, and wherein n is 2, 3, 4, or 5. These compounds are useful intermediates for the preparation of compounds having pharmacological activity.

United States Patent [191 Pike [ PGE OXIMES [75] Inventor: John E. Pike, Kalamazoo, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Aug. 20, 1971 [21] Appl. No.: 173,659

Related U.S. Application Data [62] Division of Ser. No. 673,979, Oct. 9, 1967, Pat. No.

[52] U.S. Cl. 260/514 D; 260/404; 260/404 S; 260/468 D [51] Int. Cl C07c 131/02; C070 127/11 [58] Field of Search 260/514 D, 468 D [56] References Cited UNITED STATES PATENTS l2/l966 Beal et al. 195/30 3/1970 Lapidus et al. 260/514 4/1972 Finch 260/514 OTHER PUBLICATIONS Katsube et al., Agr. Biol. Chem. 35, 1768, 1971.

Primary ExaminerRobert Gerstl Attorney, Agent, or Firm-Morris L. Nielsen; Earl C.

Spaeth [451 July 15,1975

[ 5 7] ABSTRACT This invention is a class of new organic compounds having the formula Ia CHz-Y- (cngl -cooRl Ho H OH r 8 Claims, No Drawings 1 PGE OXIMES- CROSS-REFERENCE TO RELATED APPLICATION This application is a division of US. Ser. No. 673,979 filed on Oct. 9, I967, now issued as US, Pat. No. 3,636,712.

DESCRIPTION OF THE INVENTION This invention relates to novel compositions of matter, in particular novel compounds of the formula:

wherein R is hydrogen or alkyl of l to 8 carbon atoms, 7

9 H CH -Y-(CHQ CH OH wherein X, Y, Z; m, and n are a s defined above.

The formula Icompounds are potent antagonists of epinephrine-induced mobilization of free fatty acids. According to Carlson et al., Inhibition of Lipid Mobi-. lization, Chapter 57, pages 557-574, infI-Iandbook of Physiology, Waverly Press, Baltimore, Md. (1965) at page 574, Inhibitionof lipid mobilization occurs normally in the intact organism due to interplay of nutritional, hormonal and nervous factors..ln certain diseases, e.g., vascular diseases, diabetes mellitus, and hyperthyroidism, abnormal lipid mobilization occurs and the free fatty acid content of body fluidincreases. Therefore; the formula-I; compound-sare useful in experimental medicine for both in vitro and in vivo studies to lead to the understanding, prevention, symptom alleviation, and cure ofldiseases involving abnormal lipid 'mobilization- The formula I compounds-also are. highly active in in hibitingblood platelet aggregation and thrombus for-. mation induced by various biochemical stimuli, including collagen, ADP, and, thrombin, and in causing thrombi to disaggregate, both inyitro and in vivo. For I this reason, the formula I, compounds are useful in experimental medicinefor both in .vivo and in vitro studies intended to leadto an understanding of thrombopost-operative venous thromboembolism, and athero' sclerosis:

For the above purposes,the formula I compounds are especially useful for in vivo animal studies because they are surprisingly and unexpectedly, free of side effects such as blood pressure lowering and smooth muscle stimulation exhibited by other known lipid mobilization inhibitors and platelet aggregation inhibitors. See, for example, Emmons et 21]., British Medical Journal, 2, 468 I967), Thus the response of the laboratory animal to these compounds will not be masked, altered, or influenced by these other physiological responses The formula I compounds are also useful in mammals, including mamas nasal decongestants. For this purpose, the compounds are used in a dose range about 10 ,ug to about 10 mg. per ml. of a-pharmacologically suitable'liquid vehicle or as an aerosol spray, both for topical application. v

,For the above purposes, theformula I compounds can be used in the trihydroxy form or in the form of the corresponding tricarboxyacylates, preferably in the form of the tri-lower-alkanoate. i

The formula I compounds are produced by the following sequence of reactions:

In the above reaction scheme, X, Y, Z, m, and n are as defined above. R, is hydrogen or alkyl of l to 8 carbon atoms, inclusive. Q is defined as any group of atoms transformable together with the attached nitrogen to carbonyl oxygen by reaction with nitrous acid.

The initial reactants of formula II are known in the art or can be prepared by methods known in the art. In formula II, when R, is hydrogen, m is 1, and n is 3, the carbon skeleton of prostanoic acid is described. See Horton, Experientia, 21, 113 (1965) and Samuelsson, Agnew. Chem. Inter. Ed. Eng. 4, 410 Angew. 1965). When R, is hydrogen, m is l, n is 3, and X, Y, and Z are each Cl-I CH formula 11 describes dihydroprostaglandin E, (dihydro-PGE,). Similarly, with the same limitations on R,, m, and n, and the other permissible variations in X, Y, and Z, formula II describes the other known prostaglandin E compounds, PGE,, PGE- and PGE For a discussion of the stereochemistry of these compounds which also applies to the other compoundsencompassed by formulas I, III, and IV, see Nature, 212, 38 (1966) and footnote (3) in J. Am. Chem. Soc. 88, 3133 (1966).

The compounds within the scope of formula 11 wherein R, is hydrogen and m and n are other than the above-mentioned combination of 1 and 3, respectively, are prepared by incubation of the appropriate unsaturated carboxylic acid with the enzymes of sheep seminal vesicular glands as described in US. Pat. No. 3,296,091.

The compounds within the scope of formula 11 wherein R, is alkyl of l to 8 carbon atoms, inclusive, are prepared by esterification of the corresponding free acid, i.e., R, is hydrogen, with the appropriate diazoalkane. See, for example, US. Pat. No. 3,069,322 and British specification 1,040,544.

The transformation of the initial reactants of formula II to the final desired primary alcohols of formula 1 proceeds through two novel intermediates, compounds of formulas III and IV. It will be observed that the overall transformation of II to I involves transformation of the COOR, moiety of the initial formula II reactant to the -CI-I OI-I moiety of the final formula I product. The remainder of the molecule of formula II reactant, including its stereochemical configuration, remains unchanged in the formula 1 product.

Several known reagents are available for the transformation of a COOH or --COOalkyl moiety to a CH OH moiety. Examples are lithium aluminum hydride, lithium borohydride, and diisobutyl aluminum hydride. However, those reagents also will usually reduce an isolated carbonyl group to a secondary alcohol group. Such a carbonyl group is present in the cyclopentane ring of the formula II reactant. Therefore that group must be protected with a group of atoms unreactive with the above-mentioned carboxylate reducing agents. Of equal importance is that the protective atom grouping must be such that it can be transformed back to the carbonyl group after the carboxylate reduction without alteration of the rest of the molecule.

It is well known that reactants of formula II are extraordinarily sensitive to acidic and basic conditions, being easily transformed thereby to other compounds.

It was quite surprising and unexpected therefore that nitrous acid, especially in the absence of strong acids, for example, the mineral acids, has no substantial chemical effect on reactants of formula II. In view of that discovery, the isolated carbonyl group of the formula II reactant is advantageously protected with a group of atoms which can be transformed back to the carbonyl group by reaction with nitrous acid after the carboxylate reduction.

Reagents which will transform an isolated carbonyl group to another group transformable back to the carbonyl group by reaction with nitrous acid are well known to those skilled in this art. Examples are hydroxylamine, alkoxyamines of the formula R ONH wherein R is alkyl of l to 4 carbon atoms, inclusive, semicarbazide, and thiosemicarbazide. Thereby, oximes, alkoxyoximes, semicarbazones, and thiosemicarbazones are formed. 7

The transformations of initial reactant II to first intermediate III, and of first intermediate III to second intermediate IV are carried out by methods known in the art for protecting isolated carbonyl groups and for reducing carboxyl groups or carbalkoxy groups. The transformation of second intermediate IV to final product 11 v is carried out by mixing intermediate IV with nitrous acid in the range about -10 C. to about 50 C., preferably about 10 C. to about 35 C. The nitrous acid is advantageously generated in the presence of the formula IV intermediate by dissolving or suspending the latter in a liquid alkanoic acid, e.g., acetic or propionic acid, preferably in the presence of a small amount of water, i.e., about 5 to about 25 percent water, and then adding an aqueous solution of an alkali metal or alkaline earth metal nitrite. At least one equivalent of the nitrite per equivalent of intermediate IV should beused, and it is usually advantageous to use about 2 to about 20 times the theoretical amount of nitrite. The resulting reaction mixture is maintained within the specified temperature range until thin layer chromatography of an aliquot shows intermediate IV .has disappeared. The desired formula I product is then. isolated from. the extract by methods known in the art. One useful procedure is dilution of the reaction mixture with water, and then extraction with a water-immiscible solvent, e.g., ethyl acetate. Evaporation of the extract then gives the desired product which can advantageously be purified by methods known to be useful for purification of the prostalandins, especially, preparative thin layer chromatography. See, for example, Green et al., J. Lipid Research,

Carboxyacylation of the three hydroxy groups in the novel formula I compounds of this inventioh is accomr plished by interaction of the hydroxy compound with a carboxyacylatingagent, preferably a carboxylic acid such as pyridine or triethylamine. A substantial excess of the anhydride should be used, preferably about to about 10,000 moles of anhydride per mole of the hydroxy compound reactant. The excess anhydride serves as a reaction diluent and solvent. An inert organic diluent, for example, dioxane, can be added. It is preferred to use enough of the tertiary amine to neutralize the carboxylic acid produced by the reaction.

The carboxyacylation reaction is preferably carried out in the range about 0 to about 100 C. The necessary reaction time will depend on such factors as the reaction temperature and the nature of the anhydride and tertiary amine reactants. With acetic anhydride, pyridine, and a 25 C. reaction temperature, a 12 to 24- hour reaction time should be used.

The carboxyacylated product is isolated from the reaction mixture by conventional methods. For example, the excess anhydride can be decomposed with water, and the resulting mixture acidified and then extracted with a solvent such as diethyl ether. The desired carboxyacylate will usually be extracted by the ether and is recoverable therefrom by evaporation. If desired, the carboxyacylate can be purified by conventional methods, preferably by chromatography.

The invention can be more fully understood by the following examples.

EXAMPLE 1 Oxime of 7*[ 3a-hydroxy-2B-( 3a-hydroxy-transl -octenyl )-5- oxo-la-cyelopentyl1heptanoic acid (PGE A solution of 0.2 g. of hydroxylamine hydrochloride and 0.25 g. of sodium acetate in 4 ml. of 1:1 aqueous methanol was added to a solution of 0.2 g. of PGE in 2 ml. of methanol, and the mixture was allowed to stand at 25 C. for 18 hrs. At the end of this time, the methanol was removed at room temperature under a nitrogen stream. The residual mixture was diluted with water. The crystalline solid which formed was collected by filtration, washed with water, and then dried in vacuo to give 0.19 g. of solid. That solid was recrystallized from aqueous methanol to give 0.15 g. of the oxime of PGE,; m.p. 122-124 C. On TLC, the oxime was less polar than PGE with solvent system A IX (5:5:70 acetic acidzmethanokchloroform).

Analysis:

Calcd. for C H O N: C, 65.01; H, 9.55; N, 3.79. Found: C, 64.87; H, 9.68; N, 3.74.

IR. (Principal bands; Nujol mull) 3420, 3340, 3080, 3030, 2750, 2680, 2560, 1715, 1665, 1255, 1240, 1230, 1065 and 945 cm.

Following the procedure of Example 1, the oximes of each of the following compounds were prepared:

1. dihydro-PGE 2. PGE

3. PGE;,,

4. 6-[3a-hydroxy-2B-(3a-hydroxy-trans-1-octenyl)- 5-oxol a-cyclopentyl1hexanoic acid,

5. 6-[3a-hydroxy-2B-(3a-hydroxy-trans-1-octenyl)- S-oxo- 1 a-cyclopentyl]-cis-4-hexenoic acid,

6. 8-[3a-hydroxy-2B-(3a-hydroxy-trans-l-octenyl)- 5-ox0-la-cyclopentyl1-cis-6 -octenoic acid,

7. 6-[ 3a-hydroxy-2B-(3oz-hydroxy-trans-1-heptenyl)- 5-oxol a-cyclopentyl1hexanoic acid.

Following the procedure of Example 1 but substituting for hydroxylamine hydrochloride, a stoichiometrically equivalent amount of methoxyamine hydrochloride, semicarbazide hydrochloride, or thiosemicarbazidehydrochloride, PGE, methoxime, PGE, semicarbazone, and PGE thiosemicarbazone were prepared. Similarly, substituting for PGE, the prostaglandins and analogs thereof named following Example 1, and substituting for hydroxylamine hydrochloride the stoichiometrically equivalent amount of methoxyamine hydrochloride. semicarbazide hydrochloride, or thiosemicarbazide hydrochloride, following the procedure of Example 1, the corresponding derivative of the named prostaglandins and analogs thereof were prepared.

EXAMPLE 2 Oxime of methyl 7-[3a-hydroxy-2B-( 3a-hydroxyocty1)-5-oxol acyclopentyl]heptanoate (dihydro-PGE methyl ester).

A mixture of 25 mg. of dihydro-PGE methyl ester, 1 ml. of methanol, 25 mg. of hydroxylamine hydrochloride, 30 mg. of sodium acetate and 0.5 ml. of water was allowed to stand about 18 hrs. at 25 C. The reaction mixture was concentrated at 25 C. under a stream of nitrogen. An oil separated in the residual mixture, and was extracted with dichloromethane. The dichloromethane extract was washed with water, dried, and evaporated to give an oily residue. That residue was dissolved in a small amount of a mixture of 50 percent ethyl acetate and 50 percent cyclohexane, and the solution was chromatographed on 15 g. ofsilica gel. Elution with a mixture of percent ethyl acetate and 25 percent cyclohexane and evaporation of the eluate gave 24 mg. of the oxime of dihydro-PGE, methyl ester. On TLC analysis (silica gel; ethyl acetate), one spot was obtained; slightly more polar than dihydro-PGE, methyl ester with the same solvent system.

I.R. (Principal bands, dichloromethane solution): 3300, 1745 and 930 cm.

EXAMPLE 3 Oxime of methyl 7-[ 3 a-hydroxy-2B-( 3a-hydroxy-transl -octenyl )-5- oxo-l a-cyclopentyH-cis-S-heptenoate oxime PGE methyl ester).

A solution of 25 mg. of PGE methyl ester in 1 ml. of methanol was mixed with a solution of 25 mg. of hydroxylamine hydrochloride and 30 mg. of sodium acetate in 0.5 ml. of water. The mixture was allowed to stand at 25 C. for about 18 hrs. Then, the mixture was concentrated by evaporation under a stream of nitrogen to remove the methanol. The residue was diluted with water and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated to give a residue. That residue was purified by chromatography over 15 g. of silica gel, eluting first with a mixture of 50 percent ethyl acetate and 50 percent cyclohexane, and next with a mixture of 75 percent ethyl acetate and 25 percent cyclohexane. The eluate fractions were evaporated to give the oxime of PGE methyl ester.

Following the procedure of Example 3, oximes of the following were prepared:

1. methyl 7-[ 3a-hydroxy-2B-( 3a-hydroxy-trans- 1 cis-S-octadienyl )-5-oxol a-cyclopentyH-cis-S -heptenoate (PGE methyl ester),

2. methyl 6-[3a-hydroxy-2B-(3a-hydroxy-trans-loctenyl)-5 -oxo-.1oz-cyclopentyflhexanoate,

3. methyl 6-[3a-hydroxy-2B-(3a-hydroxy-trans-1-- octenyl)--oxo-1a-cyclopentyl]-cis-4-hexenoate. 4. methyl 8-[3a hydroxy-2B-(3a-hydroxy-trans-loctenyl )-5-oxol a-cyclopentyl]-cis-6-octenoate,

5. ethyl 6-[ 3a-hydroxy-2B-( 3a-hydroxy-transl heptenyl )-5-oxo- 1 a-cyclopentyl lhexanoate.

EXAMPLE 4 Methoxime of methyl 7-[ 3oz-hydroxy-2B( 3a-hydroxyoctyl )-5-oxol acyclopentyl]heptanoate (dihydro-PGE, methyl ester).

A mixture of 25 mg. of dihydro-PGE, methyl ester, 25 mg. of methoxyamine hydrochloride and l pyridine of pyridine was allowed to stand 18 hrs. at 25 C. under nitrogen. The resulting mixture was poured into about ml. of water, and then extracted with dichloromethane. The extract was washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give a residue, which was chromatographed on silica gel as described in Example 2 to give the methoxime of dihydro-PGE methyl ester.

Following the procedure of Example 4, methoximes of the following were prepared:

1. PGE methyl ester,

2. PGE methyl ester,

3. PGE methyl ester,

4. methyl 6-[3a-hydroxy-2B-(3cx-hydroxy-trans-loctenyl )-5 -oxol a-cyclopentyl1hexanoate,

5. methyl 6-[ 3a-hydroxy-2B-( 3a-hydroxy-transl octenyl )-5 -oxol a-cyclopentyl]-cis-4-hexenoate,

6. methyl 8-[3a-hydroxy-2B-(3a-hydroxy-trans-loctenyl)-5-oxo-la-cyclopentyl]-cis-6-octenoate,

7. ethyl 6-[3a-hydroxy-2B-(3oz-hydroxy-trans-lheptenyl )-5-oxol a-cyclopentyHhexanoate.

EXAMPLE 5 semicarbazone of methyl 7-[ 3oz-hydroxy-2,B( 3a-hydroxyoctyl)-5-oxo- 1B- cyclopentyl]heptanoate (dihydro-PGE methyl ester).

A solution of mg. of dihydro-PGE methyl ester in 1 ml. of methanol was mixed with a solution of 35 mg. of semicarbazide hydrochloride and mg. of sodium acetate in 0.5 ml. of water. The mixture was allowed to stand at 25 C. for about 18 hrs. The resulting mixture was concentrated by evaporation under a stream of nitrogen to remove the methanol. The residue was diluted with water and extracted with dichloromethane. The extract was washed with water, dried over sodium sulfate, and evaporated to give a residue, which was chromatographed on silica gel as described in Example 2 to give the semicarbazone of dihydro-PGE methyl ester.

Following the procedure of Example 5, semicarbazones of the following were prepared:

1. PGE, methyl ester, 2. PGE methyl ester, 3. PGE methyl ester, 4. methyl 6-[ 3a-hydroxy-2B-( 3a-hydroxy-transl octenyl)-5'oxol a-cyclopentyl1hexanoate, 5. methyl 6-[ 3a-hydroxy-2B'-( 3a-hydroxy-transl octenyl)-5-oxol a-cyclopentyl]-cis-4-hexanoate, 6. methyl 8-[3a-hydroxy-2B-(3a hydroxy-trans-loctenyl )-5-oxol a-cyclopentyl -cis-6-octenoate, 7. ethyl 6-[3a-hydroxy-2B-(3a-hydroxy-trans-lheptenyl )-5-oxo- 1 a-cyclopentyl hexanoate.

Following the procedure of Example 5 but substituting thiosemicarbazide hydrochloride for semicarbazide hydrochloride, thiosemicarbazones of the following were prepared:

5 l. dihydro-PGE, methyl ester,

2. PGE methyl ester,

3. PGE methyl ester,

4. PGE methyl ester.

EXAMPLE 6 Oxime of 4a-hydroxy-2a-( 7-hydroxyheptyl )-3/3-(.3a-hydroxytransl-octenyl)cyclopentanone.

A solution of 250 mg. of the oxime of PGE in 17 ml. of dry tetrahydrofuran was added with stirring to a suspension of 1.2 g. of lithium aluminum hydride in 119 ml. of dry diethyl ether under nitrogen. The'mixture was stirred for 2 hrs. at 25 C. Then, excess lithium aluminum hydride was decomposed by successive additions of 50 ml. of ethyl acetate and water. The resulting mixture was filtered and the organic layer was separated, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give a crys- 2 talline residue which was triturated with diethyl ether. The diethyl ether solution was evaporated to dryness, and the residue was crystallized from a mixture of ethyl acetate and a mixture of isomeric hexanes (Skellysolve B) to give 70 mg. of the oxime of 4a-hydroxy-2a-(7- hydroxyheptyl)-3B-( 3a-hydroxy-transl -octenyl )cyclopentanone; m.p. ll8-124 C.

Analysis:

Calcd. for C H O N: C, 67.57; H, 10.49; N, 3.74. Found: C, 66.83; H, 10.44; N, 3.40.

IR. (Principal bands, Nujol mull) 3280, 1670, 1125, 1085, 1050, 1030, 1000, 975, and 955 cm.

TLC: More polar than the oxime of PGE, on the A 1X solvent system.

EXAMPLE 7 The oxime of 4a-hydroxy-2a-( 7-hydroxyhepty] )-3 B-( 3 hydtoxyoctyl )c clopentanone.

A solution of 250 mg. of the oxime of the dihydro- PGE methyl ester in 15 ml. of dry tetrahydrofuran was added with stirring to a suspension of 1.2 g. of lithium aluminum hydride in 120 ml. of dry diethyl ether under nitrogen. The mixture was stirred for about 2 hrs. at 25 C. Then, the excess lithium aluminum hydride was decomposed by additions of 50 ml. of ethyl acetate and then water. The resulting mixture was filtered and thev -oxo-1a-cyclopentyl]-cis-6-octenoic acid, ox

ime; 8. ethyl 6-[3a-hydroxy-2B-(Ba-hydroxy-trans-1- hepteny1)-5-oxo- 1 oz-cyclopentyl1h'exanoate, oxime;

6-[3oz-hydroxy-2B-(3a-hydroxy-trans-1 hepteny1)- 5-oxo-1a-cyclopenty1]hexanoic acid, oxime; there were obtained: 1

l. 4a-hydroxy-2a-( 7-hydroxyheptyl )-3B-( 30:-

hydroxyoctyl)-cyclopentanone;" oxime; 2. 4a-hydroxy-2a'( 7-hydroxyheptyl)-3B-(3ahydroxy-trans-l-octenyl)cyclopentanone, oxime;

3. 4a-hydroxy-2a-(7-hydroxy-cis-2-heptenyl)-3B- (Ba-hydroxy-trans 1-octenyl)cyc1opentanone, ox-

ime;

4. 4a-hydroxy' 2a-(7-hydroxy cis-2'-heptenyl)-3B- (3a-hydroxy-trans- 1 -cis-5-oct'adienyl )cyclopentanone, oxime; A

5. 4a-hydroxy-2a-( -hydroxyhexyl )-'3B-( 301- hydroxy-trans-l-octenyl)cyc1opentanone, oxime;

6. 4a-hydroxy-2a-(6-hydroxy-cis-4-hexenyl)-3B- (3a-hydroxy-trans-1-octenyl)cyclopentanone, cyclopentanone, oxime; 5 i

7. 4a-hydroxy-2a-(8-hydroxy-cis-6-octenyl)-3B-(3ahydroxy-transl -octenyl )cyclopentanone, oxime;

8. 4a-hydroxy-2a-(6-hydroxyhexyl)3B-(3a-hydroxytrans-1-h'eptenyl)cyclopentanone, oxime.

Following the procedure of Example 7 but substituting for the oxime of dihydro PGE, methyl ester, the methoximes, semicarbazones and thiosernicarbazones of l. dihydr o-PGE methyl e ster; dihydro PGE 2. PGE, methyl ester; PGE

3. PGE methyl ester; PGE

4. F612;, methyl ester; PGE

there are obtained the corresponding methoximes, semicarbazones, and thiosemicarbazones having the carboxy or carbalkoxy group reduced to a primary alcohol group, i.e.,

l. 4a-hydroxy-2a-( 7-hydroxyheptyl)-3,8-( 3ahydroxyoctyl)cyclopentanone, methoxime; 4a-hydroxy-2a-(7-hydroxyheptyl)-3B-(3ahydroxyoctyl)cyclopentanone, semicarbazone; and 4a-hydroxy-2 a-( 7-hydroxyheptyl)-3 B-( 3ahydroxyoctyl)cyclopentanone, thiosemicarbazone;

2. 4a-hydroxy-2a-(7-hydroxyheptyl)-3B-(3ahydroxy-trans- 1 -octenyl)cyclopentanone, methoxime; 4a-hydroxy-2a-(7-hydroxyheptyl)-3fl-(3ahydroxy-trans-l-octenyl)cyclopentanone. semicarbazone; and

10 4a-hydr oxy-2a.-(7-hydroxyheptyl)-3B-(3ahydroxy-trans-l-octenyl)cyclopentanone, I thiosemicarbazone;

3. 4a-hydro xy-2a-( 7-hydroxy-cis-2-heptenyl )-3 ,8- (3a-hydroxy-trans-1-octenyl)cyclopentanone, methoxime; 4a-hyclroxy-2a-( 7-hydroxy-cis2- heptenyl )-3 B- (3a-hydroxy-transl -octenyl )cyclopentanone, semicarbazone; and 1 4a-hydroxy-2a-(7-hydroxy-cis-2-heptenyl)-3B' (Ba-hydroxy-trans-1-octenyl)cyclopentanone. thiosemicarbazone;

4. 4a-hydroxy-2a-(7-hydroxy-cis-2-heptenyll-3l3- (3a-hydro'xy-trans-l -cis-5-octadi'enyl )cyclopentanone, m'etho'xime; 4a-hydroxy-2a-(7-hydroxy-cis-2-hepteny1)-3fi- (3a-hydrox'y-trans-1-cis-5-octadienyl)cyclopentanone, semicarbazone; and 4oZ-hydroxy-2a(7-hydroxy-cis-2-heptenyl)-3B- (3a hydroxy-trans-1-cis-5-octadienyl)cyclopentanone, thiosemicarbazone.

EXAMPLE 8 4a-Hydroxy-2oz-.( 7-h ydroxyheptyl)- 3,B- 3 oz-hydroxytrans-1 octeny1)cyclopentanone.

A solution of 146 mg. of the oxime of 4a-hydroxy- 2a-( 7-hydroxyheptyl )-3B-( 3a-hydroxy-trans- 1- octenyl)cyc1opentanone in 10 ml. of percent aqueous acetic acid was cooled to 10 C., and 5 ml. of a 10 percent aqe'uous solution of sodium nitrite was added. The mixture was allowed to stand 1 hr. at 10 C. Then themixture was allowed to warm to room temperature and treated with an additional 5 ml. of 10 percent aqueous sodium nitrite. The mixture was allowed to stand 30 min. at 25 C. Excess water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were separated, combined, washed with aqueous sodium bicarbonate and then with water, and dried over sodium sulfate. Evaporation of the solvent gave 163 mg. of a residue comprising 4a-hydroxy-2a-(7- hydroxyheptyl)-3B-(3a-hydroxy-trans-1-octenyl)cyclopentanone. The residue was dissolved in 1:1 ethyl acetatezcyclohexane and chromatographed over a column of 20 g. of acid-washed silica gel made up in 1:1 ethyl acetatezcyclohexane. The column was eluted successively with 1:1 ethyl acetatezcyclohexane, ethyl acetate, 2 percent methanol in ethyl acetate, and 5 percent ethanol in ethyl acetate. Evaporation of the eluate gave 67 mg. of crystalline fractions. This material was recrystallized from ethyl acetate to give 4oz-hydroxy-2a- (7-hydroxyheptyl)-3 B-( 3 a-hydroxy-trans-1-octenyl)- cyclopentanone; m.p. 106108 C.

Analysis:

Calcd. for C I-1 0 C, 70.54; H, 10.66. Found: C, 70.35; H, 11.08.

LR. (principal bands, Nujol mull) 3470, 3360, 1725, 1160, 1125, 1080, 1055, 1020, 990, 975 and 970 cm.

TLC: More polar than the parent oxime on the A [X solvent system.

Following the procedure of Example 8 but substituting for 4oe-hydroxy-2a-(7-hydroxyheptyl)-3B-(3ahydroxy-trans-1-octenyl)cyclopentanone, oxime, the following:

1. 4oz-hydroxy-2a-( 7-hydroxyheptyl)-3B-( 3ahydroxyoctyl)cyclopentanone, oxime;

11 4oz-hydroxy-2a-(7-hydroxy-cis-2-heptenyl)-3B- (3a-hydroxy-transl -octenyl )cyclopentanone, ox-

3. 4a-hydroxy-2a-( 7-hydroxy-cis-2-heptenyl )-3B- (3a-hydroxy-transl -cis-5-octadienyl )cyclopentanone, oxime;

4a-hydroxy-2a-( o-hydroxyhexyl )-3B-( 3ahydroxy-transl -octenyl )cyclopentanone, oxime;

5. 4a-hydroxy-2a-( 6-hydroxy-cis-4-hexenyl )-3B- (3a-hydroxy-transl -octenyl )cyclopentanone. ox-

6. 4a-hydroxy-2a-( 8-hydroxy-cis-6-octenyl )-3,B-( 3ahydroxy-transl -octenyl )cyclopentanone, oxime;

4a-hydroxy-2a-(6-hydroxyhexyl)-3B-(3ahydroxy-transl -heptenyl )cyclopentanone, oxime;

there were obtained: 7

l. 4a-hydroxy-2a-( 7-hydroxyheptyl )-3B-( 301- hydroxyoctyl)cyclopentanone;

4a-hydroxy-2a-(7-hydroxy-cis-2-heptenyl)-3B- (Ba-hydroxy-transl -octenyl )cyclopentanone;

3. 4a-hydroxy-2a-( 7-hydroxy-cis-2-heptenyl )-3B- (3a-hydroxy-transl -cis-5-octadientyl)cyclopentanone;

4a-hydroxy-20z-( 6-hydroxyhexyl)-3B-( 3ahydroxy-trans-1-octenyl)cyclopentanone; 5. 4a-hydroxy-2a-( 6-hydroxy-cis-4-hexenyl )-3 B- (3a-hydroxy-transl -octenyl )cyclopentanone; 6. 4a-hydroxy-2a-( 8-hydroxy-cis-6-octenyl)-3B-(3ahydroxy-transl -octenyl )cyclopentanone;

4a-hydroxy-2a-( 6-hydroxyhexyl )-3;6-( 3ahydroxy-trans-l-heptenyl)cyclopentanone. The above products were also obtained by following the procedures of Example 8 but replacing the starting oximes with the corresponding methoximes, semicarbazones, and thiosemicarbazones.

I claim: 1. A compound of the formula:

wherein R is hydrogen or alkyl of l to 8 carbon atoms,

. in which X is hydroxyimino or lower alkoxyimi'no,and'

inclusive, wherein O is OH, OR wherein R is alkyl of l to 4 carbon atoms, inclusive, or NH- CONH-g, wherein X is CH CH or trans-CH=CH- and both Y and Z are CH CH or wherein X is trans-CH=CH, Y is cis-CH=CH-, and Z is CH C- Hr or cis-CH=CH-, wherein m is 0, l, or 2, and wherein n is 2, 3-, 4, or 5. i

2. A compound according to claim 1 wherein m is l and n is 3.

3. A compound according to claim 1 wherein X, Y. and Z are CH CH t 4. A compound according to claim 1 wherein X is trans-CH=CH, and Y andZ are -CH CH 5. A compound according to claim 1 wherein X is trans-CH=CH, Y is cis-CH=Cl-l, and Z is "Cl-[ C- H2 6. A compound according to claim 1 wherein X is trans-CH=CH and Y and Z are cis-CH=CH-.

7. A compound of the formula: 1

wherein R is hydrogen or alkyl of l to 8 carbon atoms, inclusive; and wherein X is Cl-l-,Cl-l or trans- CH=Cl-l and both Y and Z are CH CH or wherein X is trans-CH=Cl-l, Y is cis-CH=CH, and Z is -CH CH or cis-CH=CH 8. A compound of the formula R is hydrogen, or the lower alkyl esters thereof.

pentanone, oxime UNITED STATES PATENT OFFICE QER'HHCATE ()F CORRECTION PATENT NO. 3,895,058

DATED Juty 15, 975

INVENTOR(S)I John E, Pike It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Cot umn 1, t i ne 6, "5,656,712" shout d read 5,656, 120 Cot umn 5, t i ne l2, Agnew shout d read Angew t i ne 12, ."410 Angew.

1965)" shoutd read ilo (1965) Cotumn 7, tine 13, "1

pyridine of pyridi he was" shoutd read 1 mt of pyridine was t i ne 59, 5-oxo-1B" shout d read 5-oxo-1 L Cot umn 9, t i nes 57-58, cyctopencanone, cyctopentanone, oxime" shoutd read cyctc Signed and Ercalecl this first Day Of June1976 {SEAL} A nes t:

RUTH c. msou c. MARSHALL DANN Arresting Officer Commissioner uj'larems and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein m is 1 and n is
 3. 3. A compound according to claim 1 wherein X, Y, and Z are -CH2CH2-.
 4. A compound according to claim 1 wherein X is trans-CH CH-, and Y and Z are -CH2CH2-.
 5. A compound according to claim 1 wherein X is trans-CH CH, Y is cis-CH CH-, and Z is -CH2CH2-.
 6. A compound according to claim 1 wherein X is trans-CH CH-, and Y and Z are cis-CH CH-.
 7. A compound of the formula:
 8. A COMPOUND OF THE FORMULA 